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Kynurenine

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l-Kynurenine
Skeletal formula of L-kynurenine
Ball-and-stick model of the L-kynurenine molecule as a zwitterion
Names
Preferred IUPAC name
(2S)-2-Amino-4-(2-aminophenyl)-4-oxo-butanoic acid
Other names
(S)-Kynurenine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
MeSH Kynurenine
UNII
  • InChI=1S/C10H12N2O3/c11-7-4-2-1-3-6(7)9(13)5-8(12)10(14)15/h1-4,8H,5,11-12H2,(H,14,15)/t8-/m0/s1 checkY
    Key: YGPSJZOEDVAXAB-QMMMGPOBSA-N checkY
  • c1ccc(c(c1)C(=O)C[C@@H](C(=O)O)N)N
Properties
C10H12N2O3
Molar mass 208.217 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

l-Kynurenine is a metabolite of the amino acid l-tryptophan used in the production of niacin.

Kynurenine is synthesized by the enzyme tryptophan dioxygenase, which is made primarily but not exclusively in the liver, and indoleamine 2,3-dioxygenase, which is made in many tissues in response to immune activation.[1] Kynurenine and its further breakdown products carry out diverse biological functions, including dilating blood vessels during inflammation[2] and regulating the immune response.[3] Some cancers increase kynurenine production, which increases tumor growth.[1]

Kynurenine protects the eye by absorbing UV light, especially in the UVA region (315–400 nm).[4] Kynurenine is present in the lens and retina as one of multiple tryptophan derivatives produced in the eye, including 3-hydroxykynurenine, that together provide UV protection and aid in enhancing visual acuity.[5][6] The use of kynurenine as a UV filter is consistent with its photostability and low photosensitization, owing to its efficient relaxation from the UV-induced excited state.[7] The concentration of this UV filter decreases with age,[8] and this loss of free kynurenine and the concomitant formation of relatively more photosensitizing kynurenine derivatives and kynurenine-protein conjugates may contribute to the formation of cataracts.[9][10][11]

Evidence suggests that increased kynurenine production may precipitate depressive symptoms associated with interferon treatment for hepatitis C.[12] Cognitive deficits in schizophrenia are associated with imbalances in the enzymes that break down kynurenine.[13] Blood levels of kynurenine are reduced in people with bipolar disorder.[14] Kynurenine production is increased in Alzheimer's disease[15][16] and cardiovascular disease[17] where its metabolites are associated with cognitive deficits[18] and depressive symptoms.[19] Kynurenine is also associated with tics.[20][21]

Kynureninase catabolizes the conversion of kynurenine into anthranilic acid[22] while kynurenine-oxoglutarate transaminase catabolizes its conversion into kynurenic acid. Kynurenine 3-hydroxylase converts kynurenine to 3-hydroxykynurenine.[23]

Kynurenine has also been identified as one of two compounds that makes up the pigment that gives the goldenrod crab spider its yellow color.[24]

The kynurenine pathway, which connects quinolinic acid to tryptophan. The pathway is named for the first intermediate, kynurenine, which is a precursor to kynurenic acid and 3-hydroxykynurenine.[25]

Kynurenine pathway dysfunction

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Dysfunctional states of distinct steps of the kynurenine pathway (such as kynurenine, kynurenic acid, quinolinic acid, anthranilic acid, 3-hydroxykynurenine) have been described for a number of disorders, including:[26]

Downregulation of kynurenine-3-monooxygenase (KMO) can be caused by genetic polymorphisms, cytokines, or both.[29][30] KMO deficiency leads to an accumulation of kynurenine and to a shift within the tryptophan metabolic pathway towards kynurenine acid and anthranilic acid.[31] Kynurenine-3-monooxygenase deficiency is associated with disorders of the brain (e.g. major depressive disorder, bipolar disorder, schizophrenia, tic disorders) [32] and of the liver.[20][33][34][35][36]

Drug development

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It is hypothesized that the kynurenine pathway is partly responsible for the therapeutic effect of lithium on bipolar disorder. If that is the case, it could be a target of drug discovery.[37][38]

See also

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References

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  1. ^ a b Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M, Jugold M, Guillemin GJ, Miller CL, Lutz C, Radlwimmer B, Lehmann I, von Deimling A, Wick W, Platten M (2011). "An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor". Nature. 478 (7368): 197–203. Bibcode:2011Natur.478..197O. doi:10.1038/nature10491. PMID 21976023.
  2. ^ Wang Y, Liu H, McKenzie G, Witting PK, Stasch JP, Hahn M, Changsirivathanathamrong D, Wu BJ, Ball HJ, Thomas SR, Kapoor V, Celermajer DS, Mellor AL, Keaney JF, Hunt NH, Stocker R (2010). "Kynurenine is an endothelium-derived relaxing factor produced during inflammation". Nature Medicine. 16 (3): 279–85. doi:10.1038/nm.2092. PMC 3556275. PMID 20190767.
  3. ^ Nguyen NT, Kimura A, Nakahama T, Chinen I, Masuda K, Nohara K, Fujii-Kuriyama Y, Kishimoto T (2010). "Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism". Proceedings of the National Academy of Sciences. 107 (46): 19961–6. Bibcode:2010PNAS..10719961N. doi:10.1073/pnas.1014465107. PMC 2993339. PMID 21041655.
  4. ^ Sherin, Peter S.; Grilj, Jakob; Tsentalovich, Yuri P.; Vauthey, Eric (2009-04-09). "Ultrafast Excited-State Dynamics of Kynurenine, a UV Filter of the Human Eye". The Journal of Physical Chemistry B. 113 (14): 4953–4962. doi:10.1021/jp900541b. ISSN 1520-6106.
  5. ^ Wood, Andrew M.; Truscott, Roger J. W. (1993-03-01). "UV Filters in Human Lenses: Tryptophan Catabolism". Experimental Eye Research. 56 (3): 317–325. doi:10.1006/exer.1993.1041. ISSN 0014-4835.
  6. ^ Truscott, Roger J. W.; Wood, Andrew M.; Carver, John A.; Sheil, Margaret M.; Stutchbury, Glen M.; Zhu, Jiulin; Kilby, Greg W. (1994-07-11). "A new UV-filter compound in human lenses". FEBS Letters. 348 (2): 173–176. doi:10.1016/0014-5793(94)00601-6. ISSN 0014-5793.
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